Co-prevalent infections in adults with HIV-associated cryptococcal meningitis are associated with an increased risk of death: a nested analysis of the Advancing Cryptococcal meningitis Treatment for Africa (ACTA) cohort

Background: HIV-associated cryptococcal meningitis accounts for 15% of AIDS related deaths globally. In sub-Saharan Africa, acute mortality ranges from 24% to 100%. In addition to the mortality directly associated with cryptococcosis, patients with HIV-associated cryptococcal meningitis are at risk of a range of opportunistic infections (OIs) and hospital acquired nosocomial infections (HAIs). The attributable mortality associated with co-prevalent infections in cryptococcal meningitis has not been evaluated. Methods: As part of the Advancing Cryptococcal meningitis Treatment for Africa (ACTA) trial, consecutive HIV-positive adults with cryptococcal meningitis were randomised to one of five anti-fungal regimens and followed up until 10-weeks. We conducted a retrospective case note review of ACTA participants recruited from Queen Elizabeth Central Hospital in Blantyre, Malawi to describe the range and prevalence of OIs and HAIs diagnosed, and the attributable mortality associated with these infections. Results: We describe the prevalence of OIs and HAIs in 226 participants. Baseline median CD4 count was 29 cell/mm3, 57% (129/226) were on anti-retroviral therapy. 56% (127/226) had at least one co-prevalent infection during the 10-week study period. Data were collected for 187 co-prevalent infection episodes. Suspected blood stream infection was the commonest co-prevalent infection diagnosed (34/187, 18%), followed by community-acquired pneumonia (32/187, 17%), hospital-acquired pneumonia (13/187, 7%), pulmonary tuberculosis (12/187, 6%) and confirmed blood stream infections (10/187, 5%). All-cause mortality at 10-weeks was 35% (80/226), diagnosis of an OI or HAI increased the risk of death at 10 weeks by nearly 50% (HR 1.48, 95% CI 1.01-2.17, p=0.04). Conclusion: We demonstrate the high prevalence and broad range of OIs and HAIs occurring in patients with HIV-associated cryptococcal meningitis. These co-prevalent infections are associated with a significantly increased risk of death. Whether a protocolised approach to improve surveillance and proactive treatment of co-prevalent infections would improve cryptococcal meningitis outcomes warrants further investigation

Impact of repeated four-monthly anthelmintic treatment on Plasmodium infection in preschool children: a double-blind placebo-controlled randomized trial

<p>Abstract</p> <p>Background</p> <p>Helminth infections can alter susceptibility to malaria. Studies need to determine whether or not deworming programs can impact on <it>Plasmodium </it>infections in preschool children.</p> <p>Methods</p> <p>A double-blind placebo-controlled randomised trial was conducted to investigate the impact of anthelmintic treatment on <it>Plasmodium </it>infection in children aged 12-59 months. Children were randomly assigned to receive either albendazole or placebo every four months for 12 months with a follow-up at 14 months.</p> <p>Results</p> <p>320 children (out of 1228, 26.1%) complied with all the follow-up assessments. <it>Plasmodium </it>prevalence and mean <it>Plasmodium </it>parasite density was significantly higher in the treatment group (44.9% and 2319 ± SE 511) compared to the placebo group (33.3% and 1471 ± 341) at baseline. The odds of having <it>Plasmodium </it>infection increased over time for children in both the placebo and treatment groups, however this increase was significantly slower for children in the treatment group (P = 0.002). By month 14, mean <it>Plasmodium </it>density had increased by 156% in the placebo group and 98% in the treatment group but the rate of change in <it>Plasmodium </it>density was not significantly different between the groups. The change from baseline in haemoglobin had a steeper increase among children in the treatment group when compared to the placebo group but this was not statistically significant.</p> <p>Conclusions</p> <p>Repeated four-monthly anthelminthic treatments for 14 months resulted in a significantly lower increase in the prevalence of <it>Plasmodium </it>infection in preschool children which coincided with a reduction in both the prevalence and intensity of <it>A. lumbricoides </it>infections.</p> <p>Trial Registration</p> <p>Current controlled trials ISRCTN44215995</p

Cost-effectiveness of single, high-dose, liposomal amphotericin regimen for HIV-associated cryptococcal meningitis in five countries in sub-Saharan Africa: an economic analysis of the AMBITION-cm trial

BackgroundHIV-associated cryptococcal meningitis is a leading cause of AIDS-related mortality. The AMBITION-cm trial showed that a regimen based on a single high dose of liposomal amphotericin B deoxycholate (AmBisome group) was non-inferior to the WHO-recommended treatment of seven daily doses of amphotericin B deoxycholate (control group) and was associated with fewer adverse events. We present a five-country cost-effectiveness analysis.MethodsThe AMBITION-cm trial enrolled patients with HIV-associated cryptococcal meningitis from eight hospitals in Botswana, Malawi, South Africa, Uganda, and Zimbabwe. Taking a health service perspective, we collected country-specific unit costs and individual resource-use data per participant over the 10-week trial period, calculating mean cost per participant by group, mean cost-difference between groups, and incremental cost-effectiveness ratio per life-year saved. Non-parametric bootstrapping and scenarios analyses were performed including hypothetical real-world resource use. The trial registration number is ISRCTN72509687, and the trial has been completed.FindingsThe AMBITION-cm trial enrolled 844 participants, and 814 were included in the intention-to-treat analysis (327 from Uganda, 225 from Malawi, 107 from South Africa, 84 from Botswana, and 71 from Zimbabwe) with 407 in each group, between Jan 31, 2018, and Feb 17, 2021. Using Malawi as a representative example, mean total costs per participant were US$1369 (95$1237 (1181-1293) in the control group. The incremental cost-effectiveness ratio was $128 (59-257) per life-year saved. Excluding study protocol-driven cost, using a real-world toxicity monitoring schedule, the cost per life-year saved reduced to$80 (15-275). Changes in the duration of the hospital stay and antifungal medication cost showed the greatest effect in sensitivity analyses. Results were similar across countries, with the cost per life-year saved in the real-world scenario ranging from $71 in Botswana to$121 in Uganda.InterpretationThe AmBisome regimen was cost-effective at a low incremental cost-effectiveness ratio. The regimen might be even less costly and potentially cost-saving in real-world implementation given the lower drug-related toxicity and the potential for shorter hospital stays.FundingEuropean Developing Countries Clinical Trials Partnership, Swedish International Development Cooperation Agency, Wellcome Trust and Medical Research Council, UKAID Joint Global Health Trials, and the National Institute for Health Research.TranslationsFor the Chichewa, Isixhosa, Luganda, Setswana and Shona translations of the abstract see Supplementary Materials section